mk2 inhibitor in combination with mfolfirinox for untreated metastatic pancreatic ductal adenocarcinoma

Conditions: Metastatic Pancreatic Ductal Adenocarcinoma; Pancreatic Cancer; Cancer of the Pancreas

Summary: the investigators hypothesize that mk2 inhibition may improve efficacy of mfolfirinox chemotherapy for patients with pancreatic ductal adenocarcinoma (pdac).


Eligibility criteria:
inclusion criteria: * histologically or cytologically confirmed pancreatic ductal adenocarcinoma with no prior systemic treatment for advanced or metastatic disease. patients with mixed cytology in their tumors such as adeno-squamous, mixed neuroendocrine-carcinoma are permitted if the portion of adenocarcinoma is predominant. prior adjuvant/neoadjuvant therapy (including folfirinox or mfolfirinox regimens) is allowed if progression occurred ≥ 12 months from the last dose of that therapy. * dose escalation: diagnosis of advanced inoperable or metastatic disease, where mfolfirinox (or classical folfirinox) is deemed a suitable option per the treating physician. * dose expansion: diagnosis of metastatic disease, where mfolfirinox (or classical folfirinox) is deemed a suitable option per the treating physician. * measurable disease by recist 1.1. * at least 18 years of age * ecog performance status ≤ 1. * adequate bone marrow and organ function as defined below: * absolute neutrophil count ≥ 1.5 k/cumm * platelets ≥ 100 k/cumm without transfusion within 2 weeks prior to c1d1 * hemoglobin ≥ 9.0 g/dl without transfusion within 2 weeks prior to c1d1 * total bilirubin ≤ 1.5 x iuln * ast(sgot)/alt(sgpt) ≤ 3.0 x iuln, unless there are liver metastases in which case ast and alt ≤ 5.0 x iuln * creatinine clearance \> 50 ml/min by cockcroft-gault * baseline ekg with qtcf ≤ 460 ms. * women of childbearing potential and men who are heterosexually active must agree to use adequate contraception as specified in the protocol. contraception should continue for 1 month following last dose of zunsemetinib, 6 months following last dose of irinotecan, 9 months following last dose of oxaliplatin, and/or 3 months following last dose of fluorouracil. should a woman (or the female partner of a male participant) become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. * ability to understand and willingness to sign an irb approved written informed consent document (or that of legally authorized representative, if applicable). exclusion criteria: * a history of other malignancy with the exception of 1) malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease; 2) or known indolent malignancies that do not require treatment and will likely not alter the course of treatment of metastatic pancreatic cancer. * history of allogeneic organ or stem cell transplant. * currently receiving any other investigational agents, or receipt of an investigational agent within 2 weeks or 5 half-lives of the agent, whichever is shorter. * receipt of strong and moderate cyp3a4 and cyp2c8 inhibitors (including grapefruit), strong and moderate cyp3a and cyp2c8 inducers (see appendices h and i), and drugs with qt prolonging potential within 5 half-lives of cycle 1 day 1. * known brain metastases or cns involvement, because brain metastases are often associated with poor functional status, shortened life expectancy and risk of toxicity. * a history of allergic reactions attributed to compounds of similar chemical or biologic composition to zunsemetinib, or other agents used in the study. * clinically significant neuropathy ≥ grade 2. * presence of interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected treatment-related pulmonary toxicity. * gastrointestinal conditions which could prevent absorption of zunsemetinib, in the opinion of the treating physician. * inability to swallow pills. * uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia . * pregnant and/or breastfeeding. women of childbearing potential must have a negative serum pregnancy test within 7 days of c1d1. * patients with hiv are eligible unless their cd4+ t-cell counts are \< 350 cells/mcl or they have a history of aids-defining opportunistic infection within the 12 months prior to registration. concurrent treatment with effective art according to dhhs treatment guidelines is recommended. * major surgery within 28 days prior to c1d1. major surgery refers to any surgical procedure that involves general or regional anesthesia, involves extensive resecting or altering of body parts, carries a higher risk of complications, or requires long recovery times. central line placement is allowed. * use of any live vaccines against infectious diseases (eg, influenza, varicella) within 4 weeks (28 days) of c1d1.

Keywords: pancreatic cancer zunsemetinib folfirinox